NMO Neurology Diagnostic Criteria

8172019 NMO Neurology Diagnostic Criteria

httpslidepdfcomreaderfullnmo-neurology-diagnostic-criteria 115

VIEWS amp REVIEWS

Dean M WingerchukMD FRCP(C)

Brenda Banwell MDFRCP(C)

Jeffrey L Bennett MDPhD

Philippe Cabre MD William Carroll MDTanuja Chitnis MD Jeacuterocircme de Seze MDKazuo Fujihara MD

Benjamin GreenbergMD Anu Jacob MDSven Jarius MDMarco Lana-Peixoto MDMichael Levy MD PhD Jack H Simon MDSilvia Tenembaum MD Anthony L Traboulsee

MD FRCP(C)Patrick Waters PhDKay E Wellik MLS

Brian G WeinshenkerMD FRCP(C)

Correspondence toDr Wingerchuk wingerchukdeanmayoeduor Dr Weinshenker weinbmayoedu

Editorial page 118

Supplemental dataat Neurologyorg

International consensus diagnostic criteria for neuromyelitis optica spectrumdisorders

ABSTRACT

Neuromyelitis optica (NMO) is an inflammatory CNS syndrome distinct from multiple sclerosis(MS) that is associated with serum aquaporin-4 immunoglobulin G antibodies (AQP4-IgG) PriorNMO diagnostic criteria required optic nerve and spinal cord involvement but more restrictedor more extensive CNS involvement may occur The International Panel for NMO Diagnosis (IPND)was convened to develop revised diagnostic criteria using systematic literature reviews and elec-tronic surveys to facilitate consensus The new nomenclature defines the unifying term NMOspectrum disorders (NMOSD) which is stratified further by serologic testing (NMOSD with orwithout AQP4-IgG) The core clinical characteristics required for patients with NMOSD withAQP4-IgG include clinical syndromes or MRI findings related to optic nerve spinal cord areapostrema other brainstem diencephalic or cerebral presentations More stringent clinical crite-

ria with additional neuroimaging findings are required for diagnosis of NMOSD without AQP4-IgG or when serologic testing is unavailable The IPND also proposed validation strategies andachieved consensus on pediatric NMOSD diagnosis and the concepts of monophasic NMOSDand opticospinal MS Neurology reg 2015851 ndash 13

GLOSSARY ADEM 5 acute disseminated encephalomyelitis AQP4 5 aquaporin-4 IgG 5 immunoglobulin G IPND 5 International Panelfor NMO Diagnosis LETM 5 longitudinally extensive transverse myelitis lesions MOG 5 myelin oligodendrocyte glycopro-tein MS 5 multiple sclerosis NMO 5 neuromyelitis optica NMOSD 5 neuromyelitis optica spectrum disorders SLE 5

systemic lupus erythematosus SS 5 Sjoumlgren syndrome

Neuromyelitis optica (NMO) is an inflammatory CNS disorder distinct from multiple sclerosi(MS)12 It became known as Devic disease following a seminal 1894 report3e1e2 TraditionallyNMO was considered a monophasic disorder consisting of simultaneous bilateral optic neuritiand transverse myelitis but relapsing cases were described in the 20th century3 MRI revealednormal brain scans and$ 3 vertebral segment longitudinally extensive transverse myelitis lesion(LETM) in NMO 4e3 The nosology of NMO especially whether it represented a topograph-ically restricted form of MS remained controversial

A major advance was the discovery that most patients with NMO have detectable serum antbodies that target the water channel aquaporin-4 (AQP4ndash immunoglobulin G [IgG])56 arehighly specific for clinically diagnosed NMO and have pathogenic potential7e4 ndashe6 In 2006 AQP4-IgG serology was incorporated into revised NMO diagnostic criteria that relaxed clinic

From the Departments of Neurology (DMW) and Library Services (KEW) Mayo Clinic Scottsdale AZ the Childrenrsquo

s Hospital of Phila-delphia (BB) PA the Departments of Neurology and Ophthalmology (JLB) University of Colorado Denver Aurora the Service de Neurologie(PC) Centre Hospitalier Universitaire de Fort de France Fort-de-France Martinique Department of Neurology (WC) Sir Charles Gairdner Hospital Perth Australia the Department of Neurology (TC) Massachusetts General Hospital Boston the Department of Neurology (JdS)Strasbourg University France the Department of Multiple Sclerosis Therapeutics (KF) Tohoku University Graduate School of Medicine Sendai Japan the Departments of Neurology and Neurotherapeutics (BG) University of Texas Southwestern Medical Center Dallas The Walton CentreNHS Trust (AJ) Liverpool UK the Molecular Neuroimmunology Group Department of Neurology (SJ) University Hospital HeidelbergGermany the Center for Multiple Sclerosis Investigation (ML-P) Federal University of Minas Gerais Medical School Belo Horizonte Brazil theDepartment of Neurology (ML) Johns Hopkins University Baltimore MD Portland VA Medical Center and Oregon Health and SciencesUniversity (JHS) Portland the Department of Neurology (ST) National Pediatric Hospital Dr Juan P Garrahan Buenos Aires Argentina theDepartment of Medicine (ALT) University of British Columbia Vancouver Canada Nuffield Department of Clinical Neurosciences (PW)University of Oxford UK and the Department of Neurology (BGW) Mayo Clinic Rochester MNGo to Neurologyorg for full disclosures Funding information and disclosures deemed relevant by the authors if any are provided at the end of the articleThe Article Processing Charge was paid by the Guthy-Jackson Charitable FoundationThis is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 40 (CCBY-NC-ND) which permits downloading and sharing the work provided it is properly cited The work cannot be changed in any way or usedcommercially

copy 2015 American Academy of Neurology 1

ordf 2015 American Academy of Neurology Unauthorized reproduction of this article is prohibited

Published Ahead of Print on June 19 2015 as 101212WNL0000000000001729



requirements by permitting unilateral opticneuritis or asymptomatic brain MRI lesionsbut retained the requirement for both myelitisand optic neuritis2 The 2006 criteria werevalidated in several different ethnic and racialcohorts worldwide and became the standardfor clinical and research purposes8 ndash10e5e7 ndashe15

The specificity of AQP4-IgG facilitated ob-servations that further broadened the clinicaland neuroimaging spectrum of NMO In2007 the term NMO spectrum disorders(NMOSD) was introduced to include AQP4-IgG-seropositive patients with limited or inau-gural forms of NMO (eg first-attack LETMor recurrent or bilateral optic neuritis) who were at high risk for future attacks1 TheNMOSD term also encompassed the cerebraldiencephalic and brainstem lesions that occur in a minority of patients with otherwise typicalNMO It also included AQP4-IgG-seropositivepatients with coexisting autoimmune disorders(eg systemic lupus erythematosus [SLE] or Sjoumlgren syndrome [SS]) Finally NMOSDpotentially included patients diagnosed withopticospinal MS an MS phenotype prominentin Asia and distinguished from Western MS11

Further advances have rendered the 2006 cri-teria inadequate for contemporary practice andresearch Improvement in AQP4-IgG sensitivity

has allowed for refinement of the list of non-opticospinal disease characteristics12 ndash14e16 ndashe18

Moreover loss of AQP4 immunoreactivity and astrocyte pathology in brain and spinalcord NMO lesions distinguish them fromMS lesionse19 ndashe23 Together these data sug-gest that non-opticospinal clinical and MRIcharacteristics should be incorporated intothe diagnostic criteria The term NMOSDhas also been used variably in the literatureand needs clarification3 Other outstanding issues include whether there are distinctivefeatures of pediatric NMO the current valueof the term opticospinal MS and whether monophasic NMO can be defined Finallytreatment strategies for attack prevention inNMO and MS differ Some MS immuno-therapies appear to aggravate NMO indicat-ing an imperative for early accuratediagnosis15 ndash18e24 ndashe26 The International Panelfor NMO Diagnosis (IPND) was convened

and charged with revising NMO diagnostic

criteria for clinical decision-making and toaddress the ancillary issues outlined aboveThis report represents the Panelrsquos consensusrecommendations

METHODS The IPND consisted of 18 members from 9 coun-tries and was led by 2 co-chairs (DMW BGW) It convened7 times between October 2011 and November 2013 Panel

members participated in 6 Working Groups ClinicalPresentation Neuroimaging Laboratory StudiesSerologyPediatrics Systemic Autoimmunity and Opticospinal MS

Initial consensus was reached on 2 points First NMO wouldbe subsumed into the single descriptive term NMOSD becausethe clinical behavior immunopathogenesis and treatment of pa-tients who have NMOSD are not demonstrably different than for those with NMO and patients with incomplete forms of NMOfrequently later fulfill NMO criteria1141920e27 The entrenchedand historically significant phrase NMO would be retained by using NMOSD because although the criteria would be broad-ened to include patients with neither optic neuritis or myelitis21

those syndromes eventually occur in almost all patients Secondrevised criteria would define a clinical diagnosis by integratingclinical serologic and neuroimaging data diagnosis would not bebased solely on detection of AQP4-IgG Moreover the Panelconcluded that criteria must define NMOSD in instances where AQP4-IgG serologic testing is negative or unavailable especiallybecause of the treatment implications

The IPND established several goals chief of which was devel-oping revised consensus NMOSD criteria using the best availableevidence The Clinical Presentation Working Group conductedthe primary task of establishing the spectrum and validity of clin-ical syndromes described in clinically diagnosed NMO or in asso-ciation with AQP4-IgG these data were used to establish new core clinical criteria The other Working Groups each addresseda roster of focused questions that would contribute to final diag-

nostic criteriaEach Working Group conducted a systematic literaturereview with expert librarian assistance to address its assignmentsMedical subject heading terms were used when possible andMEDLINE EMBASE and other databases were searched from1946ndash January 2012 with quarterly updates through January 15 2014 (see table e-1 on the Neurology reg Web site atNeurologyorg for search strategies and results) Two individualsindependently reviewed abstracts for relevance discordant ratings were resolved by consensus Relevant full-text articles were inde-pendently rated to identify those used for data extraction Pub-lications describing sensitivity and specificity of AQP4-IgG wereincluded if they compared groups diagnosed with clinical NMOand MS

The Clinical Presentation and Neuroimaging Working Groups compiled a list of clinical syndromes and MRI character-istics reported by more than one publication to be associated withNMOSD or AQP4-IgG Panel members rated the specificity of these characteristics for NMOSDdiagnosisusing 2 electronicsur-veys Two additional surveys presented adult case vignettes thatcontained information on clinical symptoms and signs (1ndash 3 dis-crete clinical events) with brain MRI AQP4-IgG serostatus andother potential supportivecriteria (optic nerve or spinal cord MRIfindings) or laboratory results (eg CSF data visual evoked po-tentials) Panel members assigned a diagnosis for each vignettedefinite NMOSD indeterminate (requiring further data or follow-up for confident diagnosis) or other (eg MS) A roster of potential supportive clinical MRI and laboratory criteria was

2 Neurology 85 July 14 2015




separately ranked for their influence on confidence in NMOSDdiagnosis Characteristics or scenarios endorsed by a two-thirdsPanel majority as contributing to a confident clinical diagnosis of NMOSD were used to develop separate requirements for AQP4-IgG seropositive and seronegative patients Recommendationsfrom individual Working Groups regarding pediatric NMOSDopticospinal MS systemic autoimmunity and monophasic dis-ease were summarized All IPND members endorsed the finalcriteria

RESULTS Consensus diagnostic criteria Nomenclature

The Panel reaffirmed the decision to unify the termsNMOand NMOSD Giventhe greater degree of diag-nostic uncertainty and potential heterogeneity of sero-negative NMOSD criteria were developed for bothNMOSD with AQP4-IgG and NMOSD without AQP4-IgG An additional category of NMOSD withunknown AQP4-IgG status may be used for patientsin whom serologic testing is unavailable The nomen-clature allows for future modifications based on poten-tial discovery and validation of other biomarkers in

AQP4-IgG-seronegative patients who have otherwisetypical NMOSD clinical syndromes

Clinical presentation Consensus diagnostic criteria for NMOSD are presentedin table1 Table e-2containsa glossary of terms to guide interpretation of individualcomponents of the criteria The criteria allow NMOSDdiagnosis with occurrence of at least 1 of 6 core clinicalcharacteristics and detection of AQP4-IgG The core

clinical characteristics each implicate1 of 6 CNS regionsoptic nerve19e28 ndashe31 spinal cord20e27e32 ndashe34 area postrema of the dorsal medulla2223e35 brainstem24e35 ndashe38 dien-cephalon2526e39 ndashe44 or cerebrum2728e45 ndashe48 Certain clini-cal presentations are particularly suggestive of NMOSDoptic neuritis that is simultaneously bilateral involves theoptic chiasm causes an altitudinal visual field defect orcauses severe residual visual loss (acuity 20200 or worse)4e49 ndashe51 a complete (rather than partial) spinalcord syndrome especially with paroxysmal tonicspasms429e52 and an area postrema clinical syndrome(16ndash 43 incidence) consisting of intractable hic-cups or nausea and vomiting2223e35 Clinical judgmentremains necessary because no characteristic is path-ognomonic For example altitudinal visual fielddefects may result from ischemic optic neuropathy and bilateral simultaneous optic neuritis may occur in MSe53

Diagnostic requirements are more stringent for patients in whom AQP4-IgG is not detected or for

whom testing is unavailable Such individuals mustexperience 2 or more different core clinical character-istics (ie dissemination in space affecting differentneuroanatomic regions) and other supportive MRIcharacteristics meant to enhance diagnostic specificity must also be present At least one of the clinical eventsmust be one of the 3 most common clinical character-istics of NMOSD optic neuritis transverse myelitis(additional requirement LETM MRI lesion) or anarea postrema clinical syndrome (additional require-ment associated medullary MRI lesion)222330e35

The 2 required core characteristics may occur with

a single clinical attack (eg classic Devic syndrome with simultaneous optic neuritis and acute myelitis with LETM) or multiple attacks

The Panel reached several additional conclusionsFirst at least 1 discrete clinical attack of CNS symp-toms must occur to establish NMOSD diagnosis Although asymptomatic AQP4-IgG seropositive sta-tus may exist for years before clinical NMOSD pre-sentatione54 the natural history of asymptomaticseropositivity is poorly understood SecondNMOSD diagnosis is not warranted in asymptomaticpatients with NMOSD-compatible MRI lesionsbecause the expected clinical course in such individualsis unknown Third no clinical characteristic is path-ognomonic of NMOSD Accordingly a single clinicalmanifestation is not diagnostic when AQP4-IgG is notdetected Finally no single characteristic is exclusion-ary but some are considered red flags (table 2) thatsignal the possibility of alternative diagnosese55 ndashe63

The main clinical red flagsconcern the temporal courseof the syndrome rather than the actual manifestationsMost notably a gradually progressive course of neuro-logic worsening over months to years is very uncom-

mon (1ndash

2) in NMOSD31

However after

Table 1 NMOSD diagnostic criteria for adult patients

Diagnostic criteria for NMOSD with AQP4-IgG

1 At least 1 core clinical characteristic2 Positive test for AQP4-IgG using best available detection method (cell-based assay stronglyrecommended)

3 Exclusion of alternative diagnoses a

Diagnostic criteria for NMOSD without AQP4-IgG or NMOSD with unknown AQP4-IgG status1 At least 2 core clinical characteristics occurring as a result of one or more clinical attacks

and meeting all of the following requirementsa At least 1 core clinical characteristic must be optic neuritis acute myelitis with LETM or

area postrema syndromeb Dissemination in space (2 or more different core clinical characteristics)c Fulfillment of additional MRI requirements as applicable

2 Negative tests for AQP4-IgG using best available detection method or testing unavailable3 Exclusion of alternative diagnoses a

Core clinical characteristics1 Optic neuritis2 Acute myelitis3 Area postrema syndrome episode of otherwise unexplained hiccups or nausea and vomiting4 Acute brainstem syndrome

5 Symptomatic narcolepsy or acute diencephalic clinical syndrome with NMOSD-typicaldiencephalic MRI lesions (figure 3)6 Symptomatic cerebral syndrome with NMOSD-typical brain lesions (figure 3)

Additional MRI requirements for NMOSD without AQP4-IgG and NMOSD with unknownAQP4-IgG status

1 Acute optic neuritis requires brain MRI showing (a) normal findings or only nonspecific whitematter lesions OR (b) optic nerve MRI with T2-hyperintense lesion or T1-weighted gadolinium-enhancing lesion extending over 12 optic nerve length or involving optic chiasm (figure 1)

2 Acute myelitis requires associated intramedullary MRI lesion extending over $ 3 contiguoussegments (LETM) OR $ 3 contiguous segments of focal spinal cord atrophy in patients withhistory compatible with acute myelitis (figure 1)

3 Area postrema syndrome requires associated dorsal medullaarea postrema lesions (figure 2)4 Acute brainstem syndrome requires associated periependymal brainstem lesions (figure 2)

Abbreviations AQP4 5 aquaporin-4 IgG 5 immunoglobulin G LETM 5 longitudinally exten-sive transverse myelitis lesions NMOSD 5 neuromyelitis optica spectrum disordersa See table 2 and text discussion on serologic considerations for recommendations regard-ing interpretation of clinical and serologic testing

Neurology 85 July 14 2015 3




thorough investigation for potential competing disor-ders the weight of evidence may justify NMOSDdiagnosis despite presence of 1 or more red flagsThe presence of systemic autoimmune diseases andcertain CSF data and pathologic findings (see below)may also influence NMOSD likelihood Regardlessof AQP4-IgG serologic status NMOSD should bediagnosed when criteria are fulfilled and alternativediagnoses for the clinical syndrome have beenexcluded

Neuroimaging and neurophysiologic testing MRI lesionpatterns are a major arbiter of CNS demyelinating disease differential diagnosis Several brain opticnerve and spinal cord patterns are characteristic or highly suggestive of NMOSD (table 3 figures 1ndash 3)Detection of a LETM spinal cord lesion (figure 1)

associated with acute myelitis is the most specificneuroimaging characteristic of NMOSD and is very uncommon in adult MS2 Such lesions typically involve the central gray matter and may be associated with cord swelling central hypointensity on T1- weighted sequences and enhancement following IV gadolinium administration extension of a cervical lesion into the brainstem is characteris-tic43233e35e64 ndashe67 In contrast MS cord lesions areusually about 1 vertebral segment long or less occupy peripheral white matter tracts such as the dorsal col-umns and may be asymptomatic (see table 3 for neuroimaging red flags relevant to MS and other dis-eases)34 ndash36e68 ndashe70 Although the LETM pattern is char-acteristic of NMOSD 7ndash 14 of initial and 8 of subsequent myelitis attacks in AQP4-IgG-seroposi-tive patients do not meet the LETM definition3237

Therefore NMOSD must be considered in the dif-ferential diagnosis in patients presenting with shortmyelitis lesions The timing of an individual MRI

scan must be correlated with clinical status Occasion-ally lesions of less than 3 segments are detected inNMOSD because the MRI was performed early inthe evolutionof acute myelitis or in clinical remissionduring which a LETM lesion may fragment into dis-continuous lesions37e71 Some patients with progress-ive MS have coalescent cord lesions that cansuperficially suggest a LETM patterne72 both axialand sagittal plane images should be used to judgelesion extent A LETM MRI pattern may also occur in patients with infectious granulomatous neoplas-tic and paraneoplastic diseases acute disseminated

encephalomyelitis (ADEM) spinal cord infarctionand dural arteriovenous fistulae63

During optic neuritis attacks increased signal within the optic nerve may be detected with fat-suppressed T2-weighted orbital MRI sequencestypically with gadolinium enhancement seen on T1- weighted sequences (figure 1) Bilateral optic nerveinvolvement posterior nerve predominance (especially with extension into the optic chiasm) or extensivelesions of the optic nerve (more than half of its length)are all suggestive of NMOSD (table 3)e51e73e74

According to the 2006 diagnostic scheme a nor-mal brain MRI or detection of only nonspecific whitematter lesions was a key supportive criterion2 Sixty percent of patients with NMOSD accumulate asymp-tomatic white matter lesions on longitudinal study and as many as 16 fulfill Barkhof MS MRI crite-ria333839e75 ndashe76 Detection of brain MRI white matter lesions compatible with MS does not exclude thediagnosis of NMOSD but is considered a red flagindicating that additional evidence may be requiredto confidently distinguish NMOSD from MS in indi-vidual cases3338e64e76e77 Analysis of qualitative fea-

tures of lesions assists in distinguishing NMOSD

Table 2 Red flags Findings atypical for NMOSD

Red flags (clinicallaboratory)

1 Clinical features and laboratory findings

Progressive overall clinical course (neurologic deterioration unrelated to attacks consider MS)

Atypical time to attack nadir less than 4 hours (consider cord ischemiainfarction) continualworsening for more than 4 weeks from attack onset (consider sarcoidosis or neoplasm)

Partialtransverse myelitis especially whennot associated withLETMMRI lesion (consider MS)

Presence of CSF oligoclonal bands (oligoclonal bands occur in 20 of cases of NMO vs 80 of MS)

2 Comorbidities associated with neurologic syndromes that mimic NMOSD

Sarcoidosis establishedor suggestiveclinical radiologic or laboratoryfindings thereof (egmediastinal adenopathy fever and night sweats elevated serum angiotensin convertingenzyme or interleukin-2 receptor levels)

Cancer established or with suggestive clinical radiologic or laboratory findings thereofconsider lymphoma or paraneoplastic disease (eg collapsin response mediator protein-5associated optic neuropathy and myelopathy or anti-Ma-associated diencephalic syndrome)

Chronic infection established or with suggestive clinical radiologic or laboratory findingsthereof (eg HIV syphilis)

Red flags (conventional neuroimaging)

1 Brain

a Imaging features (T2-weighted MRI) suggestive of MS (MS-typical)

Lesions with orientation perpendicular to a lateral ventricular surface (Dawson fingers)

Lesions adjacent to lateral ventricle in the inferior temporal lobe

Juxtacortical lesions involving subcortical U-fibers

Cortical lesions

b Imaging characteristics suggestive of diseases other than MS and NMOSD

Lesions with persistent ( 3 mo) gadolinium enhancement

2 Spinal cord

Characteristics more suggestive of MS than NMOSD

Lesions 3 complete vertebral segments on sagittal T2-weighted sequences

Lesions located predominantly ( 70) in the peripheral cord on axial T2-weightedsequences

Diffuse indistinct signal change on T2-weighted sequences (as sometimes seen withlongstanding or progressive MS)

Abbreviations LETM 5 longitudinally extensive transverse myelitis lesions MS 5 multiplesclerosis NMO 5 neuromyelitis optica NMOSD 5 neuromyelitis optica spectrum disordersThese are some common or key findings that should prompt thorough investigation forcompeting differential diagnoses before making a diagnosis of NMOSD





from MS First at least 7 of patients haveNMOSD-typical patterns that although not pathog-nomonic for NMOSD are considered exceptional for MS (table 3)39 including lesions of the dorsalmedullaarea postrema (figure 2)223340e36e73e78

and periependymal regions in the brainstem(figure 2)3340e36e73 and diencephalic struc-tures3940e79 or cerebral hemispherese80 (figure 3)or long lesions spanning much of the length of thecorpus callosum3941 or corticospinal tracts(figure 3)3334 Large confluent or tumefactivecerebral lesions may suggest NMOSD but in isola-tion may not be discernable from atypical MSlesions especially in AQP4-IgG-seronegative pa-tients27333942e46e81 2 e83 Second some MRI lesionpatterns considered typical of MS are rarely seen in

NMOSD including perpendicular orientation of

periventricular lesions (Dawson fingers) periven-tricular lesions located in the inferior temporal lobeand cortical lesions333843e64 Recent 7T MRI stud-ies revealed differences between NMOSD and MSspecifically regarding cortical lesions (frequent inMS but absent in NMOSD) and white matter lesions (MS plaques are periventricular and tra-versed by a central venule whereas NMOSD lesionsare subcortical and lack a central venule)e84e85

However this technology is not widely availableand further validation is needed

The Panel considered evidence for use of other imaging modalities such as nonconventional MRItechniques and optical coherence tomography andneurophysiologic tests such as visual evoked poten-tials None of these modalities were included in therevised diagnostic criteria because of concerns regard-ing lack of evidence specificity or reliability

Considerations for AQP4-IgG serologic and other

laboratory testing Technological advances in AQP4-IgG assays have improved diagnostic sensitivity without compromising specificity44 The Panelrecommended testing with cell-based serum assays(microscopy or flow cytometry-based detection) whenever possible because they optimize autoantibody detection (mean sensitivity 767 in a pooled analysis01 false-positive rate in a MS clinic cohort)12 ndash144445

However cell-based assays are not yet widely availableIndirect immunofluorescence assays and ELISAs

have lower sensitivity (mean sensitivity 63ndash 64 each)and occasionally yield false-positive results (05ndash 13

for ELISA) often at low titer12 ndash144445e86

The Panelstrongly recommended interpretative caution if such as-says are used and when low-titer positive ELISA resultsare detected in individuals who present with NMOSDclinical symptoms less commonly associatedwith AQP4-IgG (eg presentations other than recurrent optic neu-ritis myelitis with LETM or area postrema syndrome)or in situations whereclinical evidence suggests a viablealternate diagnosis Confirmatory testing is recom-mended ideally using 1 or more different AQP4-IgG assay techniques Cell-based assay has the bestcurrent sensitivity and specificity and samples may need to be referred to a specialized laboratory

Patients who fulfill NMOSD criteria but do nothave detectable AQP4-IgG despite use of the bestavailable assays or for whom serologic testing isunavailable sometimes represent a diagnostic chal-lenge46 A greater proportion of patients with NMO who have monophasic disease appear to be AQ-P4-IgG-seronegative compared to those with estab-lished relapsing disease37 A minority of patients withclinical characteristics of NMO almost all AQP4-IgG-seronegative have been reported to have detect-

able serum myelin oligodendrocyte glycoprotein

Table 3 Neuroimaging characteristics of NMOSD

Spinal cord MRI acute

LETM lesion associated with acute TM

Increased signal on sagittal T2-weighted (standard T2-weighted proton density or STIRsequences) extending over 3 or more complete vertebral segments (figure 1 A and D)

Central cord predominance (more than 70 of the lesion residing within the central graymatter) (figure 1 A ndashD)

Gadolinium enhancement of the lesion on T1-weighted sequences (no specific distribution or

pattern of enhancement is required) (figure 1 C E and F)Other characteristic features that may be detected

Rostral extension of the lesion into the brainstem (figure 1 D and E)

Cord expansionswelling

Decreased signal on T1-weighted sequences corresponding to region of increasedT2-weighted signal (figure 1F)

Spinal cord MRI chronic

Longitudinally extensive cord atrophy (sharply demarcated atrophy extending over $ 3complete contiguous vertebral segments and caudal to a particular segment of the spinalcord)with or without focal ordiffuse T2signalchange involvingthe atrophicsegment (figure 1G and H)

Optic nerve MRI

Unilateral or bilateral increased T2 signal or T1 gadolinium enhancement within optic nerve oroptic chiasm (figure 1 I ndashK) relatively long lesions (eg those extending more than half thedistance from orbit to chiasm) and those involving the posterior aspects of the optic nerves orthe chiasm are associated with NMO

Cerebral MRI NMOSD-typical brain lesion patterns (increased signal on T2-weighted MRIsequences unless otherwise noted)

Lesions involving the dorsal medulla (especially the area postrema) either small and localizedoften bilateral or contiguous with an upper cervical spinal cord lesion ( figure 2 A ndashE)

Periependymal surfaces of the fourth ventricle in the brainstemcerebellum (figure 2 F ndashH)

Lesions involving the hypothalamus thalamus or periependymal surfaces of the third ventricle(figure 3 A and B)

Large confluentunilateral or bilateral subcortical or deepwhitematterlesions (figure 3 C andD)

Long (12 of the length of the corpus callosum or greater) diffuse heterogeneous oredematous corpus callosum lesions (figure 3E)

Long corticospinal tract lesions unilateral or bilateral contiguously involving internal capsuleand cerebral peduncle (figure 3F)

Extensive periependymal brain lesions often with gadolinium enhancement (figure 3 G ndashI)

Abbreviations LETM 5 longitudinally extensive transverse myelitis lesions NMOSD 5 neu-romyelitis optica spectrum disorders STIR 5 short tau inversion recovery





(MOG) antibodies and might have different charac-teristics (younger age less frequently female and lesslikely to relapse) from those with AQP4-IgG47 ndash49e87

These findings might suggest that some AQP4-IgG-seronegative patients with clinical and neuroimaging

features of NMOSD have a different underlying

pathogenesis46 the role of MOG or other antibodiesin disease pathogenesis remains undeterminede88 TheIPND nomenclature is designed to allow incorpora-tion of cases of NMOSD associated with other vali-dated biomarkers (eg NMOSD with a specific

autoantibody)

Figure 1 Spinal cord and optic nerve MRI patterns in neuromyelitis optica spectrum disorder

Spinal cord imaging in the context of acute myelitis in neuromyelitis optica spectrum disorders (NMOSD) usually reveals alongitudinally extensive transverse myelitis (LETM) lesion extending over 3 or more vertebral segments Sagittal T2-weighted MRI of the thoracic spinal cord (A) demonstrates a typical LETM lesion involving most of the thoracic spinal cord(arrows) LETM lesions have a predilection for the central cord as shown by axial T2-weighted (B arrowhead) and T1-weighted MRI with gadolinium (C arrowhead) Cervical LETM may extend into the medulla a characteristic NMOSDpatterndemonstrated in D (arrows sagittal T2-weighted MRI) and E (arrows sagittal T1-weighted MRI with gadolinium) AcuteLETM lesions can be associated with intralesional hypointensity as shown by sagittal T1-weighted MRI (F arrow) in this

example a rim of gadolinium enhancement surrounds the hypointense region Chronic sequelae of LETM may include lon-gitudinally extensivesegmentsof spinalcord atrophy as shown by T2-weighted MRIusingsagittal(G the2 arrowheads indi-cate the atrophic segment and the top arrow indicates the normal diameter of unaffected cervical spinal cord) and axialplanes (Harrowhead shows an atrophic spinal cord) Fast spinecho fat-suppressed T2-weighted MRIin the axial (I) andcor-onal (J) planes shows increased signal throughout most the length of the left optic nerve especially its posterior portion(arrows) Axial T1-weightedMRI with gadoliniumshows enhancementof theoptic chiasm(K arrows)Theseimages arefrom2 different patients experiencing acute optic neuritis in the setting of NMOSD





Occasionally patients without detectable serum AQP4-IgG are later found to be seropositive Theremay be technical explanations in some cases but anti-body levels also increase with clinical relapses anddecrease with immunosuppressive therapy in somepatients50 Therefore retesting should be consideredbefore B-cell or antibody-targeted therapies (plasma exchange immunosuppressive drugs) are institutedand in seronegative patients who relapse51 Cases of clinical NMO in which AQP4-IgG was detected inCSF but not serum have been reported but thisappears to be rare52e89 ndashe91 Routine CSF testing of AQP4-IgG-seronegative patients is not recommen-ded but might be considered in selected seronegativecases especially those with additional confounding serum autoantibodies that may lead to uninterpret-able or false-positive assay results

The Panel considered absence of CSF oligoclonalbands as supportive evidence for NMOSD (althoughthey are sometimes transiently detectable at the time

of an attack) and presence of bands a red flag but sen-sitivity and specificity are modest453 CSF pleocytosis 50 leukocytesmL (incidence approximately 35 inNMOSD) or the presence of neutrophils or eosino-phils (either 5mL incidence 44 and 10respectively in attack-associated samples) are partic-ularly useful in distinguishing NMOSD from MS453

CSF glial fibrillary acidic protein also shows promiseas a diagnostic and prognostic biomarker but is ele-vated only for days to weeks following an attacke92e93

Pediatric NMOSD criteria The Pediatric Working

Group members noted that most clinical neuroimag-ing and laboratory characteristics of pediatric NMOSDare similar to those of adult-onset disease The femalepreponderance may be of lower magnitude ( 31femalemale ratio compared with up to 91 for adults)54e94 a greater proportion of children may havemonophasic disease5455e95 and acuteCSF abnormalitiesin pediatric MS may mimic those ordinarily consideredsuggestive of NMOSD54 ndash56 The Working Groupidentified caveats to application of the adult NMOSDcriteria in children noting especially that detection of a LETM MRI lesionassociatedwith acutemyelitis may beless specific for NMOSD Approximately 15 of children with MS may have LETM during relapseLETM can accompany monophasic ADEM and AQP4-IgG is rarely detected in children withmonophasic LETM55 In children diagnosed with ADEM according to international consensus criteria which require a polyfocal demyelinating clinicalpresentation with encephalopathy57 the presence of AQP4-IgG favors a diagnosis of NMOSD althoughprospective validation studies are required todetermine risk of recurrent NMOSD events In one

study of AQP4-IgG-seropositive children 45

Figure 2 Dorsal medulla area postrema and other brainstem lesions inneuromyelitis optica spectrum disorder

Sagittal T2-weighted fluid-attenuated inversion recovery (FLAIR) MRI shows a lesion in thedorsal medulla (A arrow) Sagittal T2-weighted (B) and T1-weighted MRI with gadolinium (C)each demonstratean acute lesion (arrows) associatedwith areapostrema clinical syndromeAxial T2-weighted FLAIR (D arrows) and T1-weighted MRI with gadolinium (E arrowheads)show dorsal medulla involvement in a patient with acute area postrema clinical syndromeAxial T2-weighted FLAIR MRI shows periependymal lesions involving the pons (F arrows)and dorsal midbrain (G arrow) Sagittal T2-weighted FLAIR MRI shows increased signal sur-rounding the fourth ventricle (H arrows)





Figure 3 Diencephalic and cerebral lesions in neuromyelitis optica spectrum disorder

A variety of brain lesion patterns are associated with neuromyelitis optica spectrum disorder Axial T2-weighted fluid-attenuated inversion recovery (FLAIR) MRI from 2 patients demonstrates lesions involving the right thalamus (A arrow)and the hypothalamus (B arrows) Axial T2-weighted FLAIR MRI shows an extensive subcortical white matter lesion(C arrow) that enhances after gadolinium administration on T1-weighted sequences (D arrow) Chronic longitudinallyextensive and linear corpus callosum lesions are depicted on sagittal T2-weighted FLAIR MRI (E arrows) CoronalT2-weighted FLAIR MRI shows longitudinal involvement of the corticospinal tract extending to the cerebral peduncleand pons (F arrows) Acute periependymal cerebral lesions from one patient are depicted using sagittal (G arrow) andaxial (H arrows) T2-weighted FLAIR MRI and axial T1-weighted MRI with gadolinium (I arrows)





experienced recurrent cerebral manifestations including encephalopathy56 Aside from these caveats thecurrently proposed diagnostic criteria for NMOSDare appropriate for pediatric patients Longitudinalobservation of the clinical course for dissemination intime and retesting the AQP4-IgG status of somechildren especially AQP4-IgG-seronegative individualspresenting with an ADEM-like event that includesoptic neuritis and LETM may be required to achieveconfident diagnosis

Monophasic NMOSD The occurrence of a second clin-ical attack which defines a relapsing disorder wasoften considered sufficient to revise the diagnosis toMS in otherwise typical NMO cases Approximately 5ndash 10 of contemporary cases are described as mon-ophasic although the optimal definition for monopha-sic NMOSD remains elusive It is unclear whether theoccurrence of bilateral optic neuritis and myelitis atinitial presentation are helpful or essential to distin-

guish such cases from relapsing NMOSD Similarlythe interval between index clinical events that is com-patible with monophasic NMO has not been consis-tently defined or adequately examined as a predictor of future clinical course Although early risk of relapse ishigh in AQP4-IgG-seropositive cases (eg about 60 within 1 year after LETM)20 cases have beendocumented in whom more than a decade elapsedbetween the index events and relapsee34

Several studies show a pattern of apparently mon-ophasic NMO being associated with a more equitablesex distribution relatively younger age at diseaseonset tendency to present with simultaneous myelitisand bilateral optic neuritis (rather than unilateraloptic nerve involvement) lower frequency of other autoimmune diseases and lower prevalence of serum AQP4-IgG compared to relapsing NMO437e96 A fraction of these patients may have other serum anti-bodies such as MOG-IgG47

The Panel concluded that monophasic NMOSDis a recognizable clinical entity but that criteria thataccurately predict long-term adherence to a mono-phasic course cannot currently be defined An intervallonger than 4 weeks between index attacks indicatesrelapsing disease The Panel also recommended thatat least 5 years (preferably longer) of relapse-free clin-ical observation after the index events be requiredbefore a monophasic course is assumed with any degree of confidence Patients who are AQP4-IgG-seropositive should be assumed to be at risk for relapse indefinitely and preventive treatment shouldbe considered even in the setting of a prolonged clin-ical remission

Systemic autoimmunity associated with NMOSD Based

on evidence from several observational studies the

Panel concluded that clinical diagnoses of SLE SSor myasthenia gravis may coexist with NMOSD clin-ical syndromes in AQP4-IgG-seropositive patientsand in fact their presence strengthens confidenceabout a NMOSD diagnosis58e97e98 The underlying cause of CNS symptoms and signs is more likely to beco-associated NMOSD than a direct complication(eg associated vasculitis) of SLE or SS In apatient suspected of having NMOSD the presenceof clinical myasthenia gravis or detectable serumacetylcholine receptor antibodies is consideredsupportive of NMOSD diagnosise99 ndashe101

Pathology Pathologic findings inbiopsyor autopsy tissueobtained from patients with AQP4-IgG-seropositiveNMOSD demonstrate loss of AQP4 immunoreactivity and evidence of perivascular complement activation inactively demyelinating lesionse20e21 Additionallyfindings supportive of astrocytopathy such as truncatedastrocyte processes or cell loss may be detected by

immunostaining for glial fibrillary acidic protein59e20

These findings in active lesions distinguish AQP4-IgG-positive NMOSD from MS data from seronegativeindividuals are not yet available59 Necrosis and lesioninfiltration with neutrophils and eosinophils aresupportive characteristicse102 but may not be presentSpinal cord lesions may differ from supraspinal lesionsin this respecte103 Serum AQP4-IgG testing usually obviates the need for biopsy in severe myelitis andleukoencephalopathy syndromese19e104e105 Aquaporin-4immunostaining is not a routine procedure in CNSbiopsy processing and is available only in select centers

The Panel does not recommend CNS biopsy butrecognizes that in atypical cases expert pathologicreview of biopsy tissue of brain or spinal cord mighthelp establish NMOSD and exclude competing diagnoses60

Opticospinal MS The term opticospinal MS wasintroduced in Japan to refer to a pattern of MS thatis relatively more common in Asian countries11e106

It was defined by recurrent optic neuritis and myelitisattacks with no brain involvement although someinvestigators allow occurrence of certain brainstemsyndromese107 The description of opticospinal MSrepresented an important milestone because it recog-nized that there was a relapsing illness distinct fromconventional MS that selectively targeted the opticnerve and spinal cord at a time when relapses weredeemed to be incompatible with a diagnosis of NMOin both Western countries and Japan

Contemporary NMO criteria that include MRIcriteria for length of spinal cord lesions and detectionof AQP4-IgG are more specific than historical optico-spinal MS criteria Clinicians and investigators in

many Asian countries now use the term NMO rather Neurology 85 July 14 2015 9






review of the manuscript for important intellectual content A Jacob par-ticipated in the acquisition and analysis of data and writing and criticalreview of the manuscript for important intellectual content S Jariusparticipated in the acquisition and analysis of data and writing andcritical review of the manuscript for important intellectual content MLana-Peixoto participated in the acquisition and analysis of data and writ-ing and critical review of the manuscript for important intellectual con-tent M Levy participated in the acquisition and analysis of data and writing and critical review of the manuscript for important intellectualcontent J Simon participated in the acquisition and analysis of data and writing and critical review of the manuscript for important intellec-

tual content S Tenembaum participated in the acquisition and analysisof data and writing and critical review of the manuscript for importantintellectual content A Traboulsee participated in the acquisition andanalysis of data and writing and critical review of the manuscript for important intellectual content P Waters participated in the acquisitionand analysis of data and writing and critical review of the manuscriptfor important intellectual content K Wellik participated in the acquisi-tion and analysis of data and writing and critical review of the manuscriptfor important intellectual content B Weinshenker participated in study concept and design obtaining funding acquisition and analysis of datadrafting and revising the manuscript and coordinating the study

ACKNOWLEDGMENTThe authors thank the Guthy-Jackson Charitable Foundation for organi-zational and financial support Dr Katja van Herle Dr Valerie PasquettoDr Michael Yeaman and Jacinta Behne for assistance Prof Jun-ichi KiraKyushu University for initial IPND discussions and Amy Clayton andKatrina Rivera for administrative assistance and Cory Poetzl and BonnieSchimek for media support services (Mayo Clinic Scottsdale AZ)

STUDY FUNDINGThe International Panel for Neuromyelitis Optica Diagnosis was sup-ported by the Guthy Jackson Charitable Foundation

DISCLOSURED Wingerchuk has received research support from Alexion TerumoBCTand the Guthy Jackson Charitable Foundation receives financial compensa-tion for participation on a relapse adjudication panel for MedImmune hasserved as a consultant to Alexion MedImmune and Chugai Pharmaceuti-cals and has served as co-Editor-in-Chief of The Neurologist B Banwellserves as an advisor on clinical trial design for Biogen Idec Sanofi Teva Neuroscience and Novartis Dr Banwell provides consultant services for Novartis Dr Banwell is an Editor-in-Chief for Multiple Sclerosis and Related Disorders J Bennett serves as a consultant for Novartis Pharmaceuticals Alnaylam Pharmaceuticals MedImmune Chugai Pharmaceuticals EMDSerono Abbott Pharmaceuticals Genentech Genzyme and Questcor Phar-maceuticals receives license royalties for a patent re Compositions andMethods for the Treatment of Neuromyelitis Optica and serves onthe editorial boards of the Multiple Sclerosis Journal and Journal of Neuro- ophthalmology P Cabre reports no disclosures relevant to the manuscript W Carroll has received travel assistance andor honoraria from and providedadvice to Bayer Schering Pharma Biogen Idec Novartis Genzyme Sanofi- Aventis CSL and Merck-Serono T Chitnis has performed consulting for Biogen Idec and Novartis Has received support for research activities fromNovartis and Merck-Serono J de Seze has performed consulting for AlexionChugai and Novartis K Fujihara serves on scientific advisory boards for Bayer Schering Pharma Biogen Idec Mitsubishi Tanabe Pharma Corpora-tion Novartis Pharma Chugai Pharmaceutical Ono Pharmaceutical NihonPharmaceutical Merck Serono Alexion Pharmaceuticals Medimmune andMedical Review has received funding for travel and speaker honoraria fromBayer Schering Pharma Biogen Idec Eisai Inc Mitsubishi Tanabe Pharma Corporation Novartis Pharma Astellas Pharma Inc Takeda PharmaceuticalCompany Limited Asahi Kasei Medical Co Daiichi Sankyo and NihonPharmaceutical serves as an editorial board member of Clinical and Exper- imental Neuroimmunology (2009ndash present) and an advisory board member of Sri Lanka Journal of Neurology has received research support from Bayer Schering Pharma Biogen Idec Japan Asahi Kasei Medical The Chemo-Sero-Therapeutic Research Institute Teva Pharmaceutical Mitsubishi Ta-nabe Pharma Teijin Pharma Chugai Pharmaceutical Ono Pharmaceutical

Nihon Pharmaceutical and Genzyme Japan and is funded as the secondary investigator (22229008 2010ndash 2015) by the Grants-in-Aid for ScientificResearch from the Ministry of Education Science and Technology of Japanand as the secondary investigator by the Grants-in-Aid for Scientific Researchfrom the Ministry of Health Welfare and Labor of Japan (2010ndash present) BGreenberg has received compensation for consulting services from ChugaiGSK Biogen Novartis DioGenix and Amplimmune and receives researchsupport from the Guthy Jackson Charitable Foundation A Jacob hasreceived honoraria for clinical trial advisory boards and speaker rsquos fees fromChugai Alexion and Biogen S Jarius has been supported by a researchgrant from the European Committee for Treatment and Research in Mul-

tiple Sclerosis (ECTRIMS) S Jariusrsquo

department has been supported by research grants from Merck Serono and from the Dietmar Hopp Foundationand by a travel grant from the Guthy-Jackson Charitable Foundation MLana-Peixoto has served on a scientific advisory board for Novartis M Levyis supported by research funds from the NIH Guthy Jackson CharitableFoundation Viropharma Acorda ApoPharma and Sanofi He has receivedadvisory compensation from GlaxoSmithKline and Asterias J Simon hasserved as a consultant and received research support from Biogen Idec STenembaum has received honoraria for speaking from Biogen Idec andMerck Serono and for participation in an advisory group for Biogen IdecMerck Serono and Teva Pharmaceutical Ind A Traboulsee has receivedgrant funding from the MS Society of Canada the Canadian Institute for Health Research the Lotte and John Hecht Foundation the Vancouver Hospital Foundation Bayer Roche and Biogen He has served on the data safety monitoring board for Merck Serono and a clinical trial steering com-

mittee for Roche He has received honoraria or travel grants from BiogenTeva Canada Innovation Roche MerckEMD Serono and Chugai Phar-maceuticals P Waters is a named inventor on patents for antibody assays(no 20120114666 application no 13108550) and has received royaltiesHe has received a speaker honorarium from Biogen Idec and Euroimmun AG K Wellik reports no disclosures relevant to the manuscript B Wein-shenker has received a research grant from the Guthy Jackson FoundationHe receives royalties from RSR Ltd for a technology license related to a testfor aquaporin-4 autoantibodies for diagnosis of neuromyelitis optica Hereceives financial compensation for service on data safety monitoring com-mittees for Novartis Biogen Idec and Mitsubishi pharmaceutical companiesfor MS clinical trials and on a relapse adjudication panel for MedImmunePharmaceuticals for NMO clinical trials He served as a consultant for GlaxoSmithKline Elan Ono Chugai Chord and Alexion pharmaceuticalcompanies and for Asahi Kasei Medical Company all for activities related to

design of clinical trials for neuromyelitis optica He serves on editorial boardsfor Neurology reg the Canadian Journal of Neurological Sciences and the Turkish Journal of Neurology Go to Neurologyorg for full disclosures

Received September 30 2014 Accepted in final form January 28 201

REFERENCES1 Wingerchuk DM Lennon VA Lucchinetti CF

Pittock SJ Weinshenker BG The spectrum of neuromy-elitis optica Lancet Neurol 20076805ndash 815

2 Wingerchuk DM Lennon VA Pittock SJ Lucchinetti CF Weinshenker BG Revised diagnostic criteria for neuromy-elitis optica Neurology 2006661485ndash 1489

3 Jarius S Wildemann B The history of neuromyelitis op-tica J Neuroinflammation 2013108

4 Wingerchuk DM Hogancamp WF OrsquoBrien PC Weinshenker BG The clinical course of neuromyelitis op-tica (Devicrsquos syndrome) Neurology 1999531107ndash 1114

5 Lennon VA Wingerchuk DM Kryzer TJ et al A serumautoantibody marker of neuromyelitis optica distinctionfrom multiple sclerosis Lancet 20043642106ndash 2112

6 Lennon VA Kryzer TJ Pittock SJ Verkman ASHinson SR IgG marker of optic-spinal multiple sclerosisbinds to the aquaporin-4 water channel J Exp Med 2005202473ndash 477

7 Papadopoulos MC Verkman AS Aquaporin 4 and neu-romyelitis optica Lancet Neurol 201211535ndash 544





8 Asgari N Lillevang ST Skejoe HP Falah M Stenager EKyvik KO A population-based study of neuromyelitisoptica in Caucasians Neurology 2011761589ndash 1595

9 Cabre P Migration and multiple sclerosis the French West Indies experience J Neurol Sci 2007262117ndash 121

10 Cabrera-Gomez JA Kurtzke JF Gonzalez-Quevedo ALara-Rodriguez R An epidemiological study of neuromy-elitis optica in Cuba J Neurol 200925635ndash 44

11 Kuroiwa Y Shibasaki H Epidemiologic and clinical studiesof multiple sclerosis in Japan Neurology 1976268ndash 10

12 Jarius S Wildemann B Aquaporin-4 antibodies (NMO-IgG) as a serological marker of neuromyelitis optica a crit-ical review of the literature Brain Pathol 201323661ndash 683

13 Waters PJ McKeon A Leite MI et al Serologic diagnosisof NMO a multicenter comparison of aquaporin-4-IgGassays Neurology 201278665ndash 671

14 Sato DK Nakashima I Takahashi T et al Aquaporin-4antibody-positive cases beyond current diagnostic criteria for NMO spectrum disorders Neurology 2013802210ndash 2216

15 Kimbrough DJ Fujihara K Jacob A et al Treatment of neuromyelitis optica review and recommendations MultScler Relat Disord 20121180ndash 187

16 Kleiter I Hellwig K Berthele A et al Failure of natalizu-

mab to prevent relapses in neuromyelitis optica ArchNeurol 201269239ndash 24517 Min JH Kim BJ Lee KH Development of extensive

brain lesions following fingolimod (FTY720) treatmentin a patient with neuromyelitis optica spectrum disorderMult Scler 201218113ndash 115

18 Papeix C Vidal JS de Seze J et al Immunosuppressivetherapy is more effective than interferon in neuromyelitisoptica Mult Scler 200713256ndash 259

19 Matiello M Lennon VA Jacob A et al NMO-IgG pre-dicts the outcome of recurrent optic neuritis Neurology 2008702197ndash 2200

20 Weinshenker BG Wingerchuk DM Vukusic S et alNeuromyelitis optica IgG predicts relapse after longitudi-nally extensive transverse myelitis Ann Neurol 200659566ndash 569

21 Nagaishi A Takagi M Umemura A et al Clinical featuresof neuromyelitis optica in a large Japanese cohort com-parison between phenotypes J Neurol Neurosurg Psychi-atry 2011821360ndash 1364

22 Misu T Fujihara K Nakashima I Sato S Itoyama YIntractable hiccup and nausea with periaqueductal lesionsin neuromyelitis optica Neurology 2005651479ndash 1482

23 Apiwattanakul M Popescu BF Matiello M et al Intrac-table vomiting as the initial presentation of neuromyelitisoptica Ann Neurol 201068757ndash 761

24 Kremer L Mealy M Jacob A et al Brainstem manifes-

tations in neuromyelitis optica a multicenter study of 258patients Mult Scler 201420843ndash 847

25 Poppe AY Lapierre Y Melancon D et al Neuromyelitisoptica with hypothalamic involvement Mult Scler 200511617ndash 621

26 Vernant JC Cabre P Smadja D et al Recurrent opticneuromyelitis with endocrinopathies a new syndromeNeurology 19974858ndash 64

27 Kim W Kim SH Lee SH Li XF Kim HJ Brain abnor-malities as an initial manifestation of neuromyelitis optica spectrum disorder Mult Scler 2011171107ndash 1112

28 Magana SM Matiello M Pittock SJ et al Posterior reversible encephalopathy syndrome in neuromyelitis op-tica spectrum disorders Neurology 200972712ndash 717

29 Kim SM Go MJ Sung JJ Park KS Lee KW Painfultonic spasm in neuromyelitis optica incidence diagnosticutility and clinical characteristics Arch Neurol 2012691026ndash 1031

30 Popescu BF Lennon VA Parisi JE et al Neuromyelitisoptica unique area postrema lesions nausea vomiting andpathogenic implications Neurology 2011761229ndash 1237

31 Wingerchuk DM Pittock SJ Lucchinetti CF Lennon VA Weinshenker BG A secondary progressive clinical course isuncommon in neuromyelitis optica Neurology 200768

603ndash 60532 Flanagan EP Weinshenker BG Krecke KN et al Short

myelitis lesions in aquaporin-4-IgGndash positive neuromyelitisoptica spectrum disorders JAMA Neurol 20157281ndash 87

33 Kim W Park MS Lee SH et al Characteristic brainmagnetic resonance imaging abnormalities in central ner-vous system aquaporin-4 autoimmunity Mult Scler 2010161229ndash 1236

34 Huh SY Min JH Kim W et al The usefulness of brainMRI at onset in the differentiation of multiple sclerosisand seropositive neuromyelitis optica spectrum disordersMult Scler 201420695ndash 704

35 Bourre B Zephir H Ongagna JC et al Long-term follow-

up of acute partial transverse myelitis Arch Neurol 201269357ndash 36236 Scott TF Kassab SL Pittock SJ Neuromyelitis optica IgG

status in acute partial transverse myelitis Arch Neurol2006631398ndash 1400

37 Jarius S Ruprecht K Wildemann B et al Contrasting disease patterns in seropositive and seronegative neuromy-elitis optica a multicentre study of 175 patients J Neuroinflammation 2012914

38 Matthews L Marasco R Jenkinson M et al Distinctionof seropositive NMO spectrum disorder and MS brainlesion distribution Neurology 2013801330ndash 1337

39 Pittock SJ Lennon VA Krecke K Wingerchuk DMLucchinetti CF Weinshenker BG Brain abnormalitiesin neuromyelitis optica Arch Neurol 200663390ndash 396

40 Pittock SJ Weinshenker BG Lucchinetti CF Wingerchuk DM Corboy JR Lennon VA Neuromyelitisoptica brain lesions localized at sites of high aquaporin 4expression Arch Neurol 200663964ndash 968

41 Nakamura M Misu T Fujihara K et al Occurrence of acute large and edematous callosal lesions in neuromyelitisoptica Mult Scler 200915695ndash 700

42 Magana SM Pittock SJ Lennon VA Keegan BM Weinshenker BG Lucchinetti CF Neuromyelitisoptica IgG serostatus in fulminant central nervous systeminflammatory demyelinating disease Arch Neurol 200966964ndash 966

43 Kim JE Kim SM Ahn SW et al Brain abnormalities inneuromyelitis optica J Neurol Sci 201130243ndash 48

44 Waters P Pittock SJ Bennett JL Jarius S Weinshenker BG Wingerchuk DM Evaluation of aquaporin-4 antibody assays Clin Exp Neuroimmunol20145290ndash 303

45 Pittock SJ Lennon VA Bakshi N et al Seroprevalence of aquaporin-4ndash IgG in a northern California population rep-resentative cohort of multiple sclerosis JAMA Neurol2014711433ndash 1436

46 Marignier R Bernard-Valnet R Giraudon P et al Aquaporin-4 antibody-negative neuromyelitis optica dis-tinct assay sensitivity-dependent entity Neurology 2013802194ndash 2200





47 Kitley J Woodhall M Waters P et al Myelin-oligodendrocyteglycoprotein antibodies in adults with a neuromyelitisoptica phenotype Neurology 2012791273ndash 1277

48 Kitley J Waters P Woodhall M et al Neuromyelitisoptica spectrum disorders with aquaporin-4 and myelin-oligodendrocyte glycoprotein antibodies a comparativestudy JAMA Neurol 201471276ndash 283

49 Sato DK Callegaro D Lana-Peixoto MA et al Distinctionbetween MOG antibody-positive and AQP4 antibody-positiveNMO spectrum disorders Neurology 201482474ndash 481

50 Jarius S Aboul-Enein F Waters P et al Antibody toaquaporin-4 in the long-term course of neuromyelitis op-tica Brain 20081313072ndash 3080

51 Jiao Y Fryer JP Lennon VA et al Updated estimate of AQP4-IgG serostatus and disability outcome in neuromy-elitis optica Neurology 2013811197ndash 1204

52 McKeon A Pittock SJ Lennon VA CSF complementsserum for evaluating paraneoplastic antibodies andNMO-IgG Neurology 2011761108ndash 1110

53 Jarius S Paul F Franciotta D et al Cerebrospinal fluidfindings in aquaporin-4 antibody positive neuromyelitisoptica results from 211 lumbar punctures J Neurol Sci201130682ndash 90

54 Collongues N Marignier R Zephir H et al Long-termfollow-up of neuromyelitis optica with a pediatric onsetNeurology 2010751084ndash 1088

55 Banwell B Tenembaum S Lennon VA et al Neuromy-elitis optica ndash IgG in childhood inflammatory demyelinat-ing CNS disorders Neurology 200870344ndash 352

56 McKeon A Lennon VA Lotze T et al CNS aquaporin-4autoimmunity in children Neurology 20087193ndash 100

57 Krupp LB Tardieu M Amato MP et al InternationalPediatric Multiple Sclerosis Study Group criteria for pedi-

atric multiple sclerosis and immune-mediated central ner-vous system demyelinating disorders revisions to the 2007definitions Mult Scler 2013191261ndash 1267

58 Wingerchuk DM Weinshenker BG The emerging rela-tionship between neuromyelitis optica and systemic rheu-matologic autoimmune disease Mult Scler 2012185ndash 10

59 Lucchinetti CF Guo Y Popescu BF Fujihara KItoyama Y Misu T The pathology of an autoimmuneastrocytopathy lessons learned from neuromyelitis opticaBrain Pathol 20142483ndash 97

60 Popescu BFG Guo Y Jentoft ME et al Diagnostic utility of aquaporin-4 in the analysis of active demyelinating le-sions Neurology 201584148ndash 158





DOI 101212WNL0000000000001729 published online June 19 2015 Neurology

Dean M Wingerchuk Brenda Banwell Jeffrey L Bennett et alInternational consensus diagnostic criteria for neuromyelitis optica spectrum disorders

This information is current as of June 19 2015

rights reserved Print ISSN 0028-3878 Online ISSN 1526-632X1951 it is now a weekly with 48 issues per year Copyright copy 2015 American Academy of Neurology All

reg is the official journal of the American Academy of Neurology Published continuously since Neurology



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Subspecialty Collections

httpwwwneurologyorgcgicollectiontransverse_myelitisTransverse myelitis

httpwwwneurologyorgcgicollectionoptic_neuritisOptic neuritis see Neuro-ophthalmologyOptic Nerv e

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requirements by permitting unilateral opticneuritis or asymptomatic brain MRI lesionsbut retained the requirement for both myelitisand optic neuritis2 The 2006 criteria werevalidated in several different ethnic and racialcohorts worldwide and became the standardfor clinical and research purposes8 ndash10e5e7 ndashe15

The specificity of AQP4-IgG facilitated ob-servations that further broadened the clinicaland neuroimaging spectrum of NMO In2007 the term NMO spectrum disorders(NMOSD) was introduced to include AQP4-IgG-seropositive patients with limited or inau-gural forms of NMO (eg first-attack LETMor recurrent or bilateral optic neuritis) who were at high risk for future attacks1 TheNMOSD term also encompassed the cerebraldiencephalic and brainstem lesions that occur in a minority of patients with otherwise typicalNMO It also included AQP4-IgG-seropositivepatients with coexisting autoimmune disorders(eg systemic lupus erythematosus [SLE] or Sjoumlgren syndrome [SS]) Finally NMOSDpotentially included patients diagnosed withopticospinal MS an MS phenotype prominentin Asia and distinguished from Western MS11

Further advances have rendered the 2006 cri-teria inadequate for contemporary practice andresearch Improvement in AQP4-IgG sensitivity

has allowed for refinement of the list of non-opticospinal disease characteristics12 ndash14e16 ndashe18

Moreover loss of AQP4 immunoreactivity and astrocyte pathology in brain and spinalcord NMO lesions distinguish them fromMS lesionse19 ndashe23 Together these data sug-gest that non-opticospinal clinical and MRIcharacteristics should be incorporated intothe diagnostic criteria The term NMOSDhas also been used variably in the literatureand needs clarification3 Other outstanding issues include whether there are distinctivefeatures of pediatric NMO the current valueof the term opticospinal MS and whether monophasic NMO can be defined Finallytreatment strategies for attack prevention inNMO and MS differ Some MS immuno-therapies appear to aggravate NMO indicat-ing an imperative for early accuratediagnosis15 ndash18e24 ndashe26 The International Panelfor NMO Diagnosis (IPND) was convened

and charged with revising NMO diagnostic

criteria for clinical decision-making and toaddress the ancillary issues outlined aboveThis report represents the Panelrsquos consensusrecommendations

METHODS The IPND consisted of 18 members from 9 coun-tries and was led by 2 co-chairs (DMW BGW) It convened7 times between October 2011 and November 2013 Panel

members participated in 6 Working Groups ClinicalPresentation Neuroimaging Laboratory StudiesSerologyPediatrics Systemic Autoimmunity and Opticospinal MS

Initial consensus was reached on 2 points First NMO wouldbe subsumed into the single descriptive term NMOSD becausethe clinical behavior immunopathogenesis and treatment of pa-tients who have NMOSD are not demonstrably different than for those with NMO and patients with incomplete forms of NMOfrequently later fulfill NMO criteria1141920e27 The entrenchedand historically significant phrase NMO would be retained by using NMOSD because although the criteria would be broad-ened to include patients with neither optic neuritis or myelitis21

those syndromes eventually occur in almost all patients Secondrevised criteria would define a clinical diagnosis by integratingclinical serologic and neuroimaging data diagnosis would not bebased solely on detection of AQP4-IgG Moreover the Panelconcluded that criteria must define NMOSD in instances where AQP4-IgG serologic testing is negative or unavailable especiallybecause of the treatment implications

The IPND established several goals chief of which was devel-oping revised consensus NMOSD criteria using the best availableevidence The Clinical Presentation Working Group conductedthe primary task of establishing the spectrum and validity of clin-ical syndromes described in clinically diagnosed NMO or in asso-ciation with AQP4-IgG these data were used to establish new core clinical criteria The other Working Groups each addresseda roster of focused questions that would contribute to final diag-

nostic criteriaEach Working Group conducted a systematic literaturereview with expert librarian assistance to address its assignmentsMedical subject heading terms were used when possible andMEDLINE EMBASE and other databases were searched from1946ndash January 2012 with quarterly updates through January 15 2014 (see table e-1 on the Neurology reg Web site atNeurologyorg for search strategies and results) Two individualsindependently reviewed abstracts for relevance discordant ratings were resolved by consensus Relevant full-text articles were inde-pendently rated to identify those used for data extraction Pub-lications describing sensitivity and specificity of AQP4-IgG wereincluded if they compared groups diagnosed with clinical NMOand MS

The Clinical Presentation and Neuroimaging Working Groups compiled a list of clinical syndromes and MRI character-istics reported by more than one publication to be associated withNMOSD or AQP4-IgG Panel members rated the specificity of these characteristics for NMOSDdiagnosisusing 2 electronicsur-veys Two additional surveys presented adult case vignettes thatcontained information on clinical symptoms and signs (1ndash 3 dis-crete clinical events) with brain MRI AQP4-IgG serostatus andother potential supportivecriteria (optic nerve or spinal cord MRIfindings) or laboratory results (eg CSF data visual evoked po-tentials) Panel members assigned a diagnosis for each vignettedefinite NMOSD indeterminate (requiring further data or follow-up for confident diagnosis) or other (eg MS) A roster of potential supportive clinical MRI and laboratory criteria was

















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Documents

NMO Neurology Diagnostic Criteria